Академический Документы
Профессиональный Документы
Культура Документы
Page 1 of 8
Yet the stock ran to $36 in May, a price point at which the company was thrilled to execute a fat
follow-on offering.
The price run was fueled when AVXS was granted the FDA drug designation of "Breakthrough
Therapy", because SMA Type 1 is truly a life-and-death condition. However, this designation
does not grant automatic validation of a drug candidate (see below). Then, with the market in
a frenzy to find Sarepta "me-too" stories, the stock ran over $65, and now hovers around $50.
"How?", you ask? Simple! The market went nuts on the run-up of false-comp Sarepta (SRPT),
which is up 500% since January on a surprise, controversial and emotionally-driven FDA
approval for a similarly rare indication (Duchenne Muscular Dystrophy), despite questionable
efficacy data for Sarepta's drug. Then the market went looking for "me-too" phenomena stocks,
and found this one.
Their main competitor (Nusinersen from Biogen and Ionis) is dominating the
science behind a real treatment of treating Spinal Muscular Atrophy.
In April, Ionis and Biogen's Nusinersen met all primary endpoints in a Phase
2 study, with no safety or tolerability concerns identified.
http://ir.ionispharma.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=2158750
Then just months later, in August, Ionis and Biogen's study met its primary
endpoint in an interim analysis of its Phase 3 trial for both survival and
motor milestone responses:
Citron Dissects AveXis
Page 2 of 8
Ionis and Biogen have plans to obtain FDA approval for Nusinersen in Q1 2017.
"The companies now plan to file for marketing approval with regulatory authorities in the
next few months and are working to open an expanded access program (EAP) this Autumn,
to patients with infantile onset SMA (consistent with Type 1) prior to potential regulatory
approval. "
.
http://www.smatrust.org/wp-content/uploads/2016/08/EU-Community-Statement_FINALVCB.pdf
Meanwhile, AveXis stock is over twice the price of its initial offering despite shareholders
biggest risk having become a reality: Nusinersen works, safely and effectively. It will most likely
earn FDA and European approval.
This is the worst possible news for AveXis shareholders and was even called out as a risk factor
in AveXiss corporate filings:
From the AveXis IPO:
"We face significant competition in an environment of rapid technological change and the
possibility that our competitors may achieve regulatory approval before us or develop
therapies that are more advanced or effective than ours, which may adversely affect our
financial condition and our ability to successfully market or commercialize AVXS-101."
https://www.sec.gov/Archives/edgar/data/1652923/000104746916010121/a2227319z424b4.htm
In fact, AveXis changed this language in their follow-on offering, to address explicitly the
looming risk of a Nusinersen approval:
"* availability of competing therapies and clinical trials, including Ionis
Pharmaceuticals, Inc. and Biogen's proposed global expanded access program for
Nusinersen for eligible patients with SMA Type 1"
https://www.sec.gov/Archives/edgar/data/1652923/000104746916015407/a2229653z424b4.htm
With the news since IPO, it's unimaginable that this stock has run
higher than its IPO price. How can it be trading at levels 50% higher
than its secondary price of $34?
The writer of this article is a parent. I am sure many of the readers are as well. If you happen to
bear the misfortune of a baby born with Type 1 SMA, are you going to treat your child with a
drug with FDA approval based on robust multi-site clinical data, or are your going to enroll your
child into an experimental gene therapy trial executed at just one clinic? It would be
irresponsible, unethical, and should be illegal for anyone to put his or her baby on any
alternative treatment. This condition requires early treatment, with good clinical outcomes
reflective of early treatment.
In a post-Nusinersen approval world, AveXis faces severe risks of NEVER being able to complete
full clinical studies. (NOTE: In order to test the efficacy of AVXS-101, babies treated with
Nusinersen would obviously never be candidates for enrollment.)
Citron Dissects AveXis
Page 3 of 8
While the word breakthrough might seem like the FDA has committed to a fast-track to
approval this is simply not the case. If a drug fits the need of a serious or life threatening
disease with the potential of substantial treatment advantages over existing treatments, it can
receive Breakthrough Therapy status in order to streamline its approval path. Maybe the FDA
should rethink that word, as investors are easy confuse its true meaning.
A Bloomberg story that best explains the "Breakthrough Therapy" designation:
The FDA can expedite reviews for drugs when there is no alternative for patients with serious
and/or life-threatening conditions. Without head-to-head testing against Nusinersen, and its
overwhelming approval looming, considering AveXis's clinical trial evidence is so thin, the
motivation to expedite AVXS-101's path to approval simply evaporates.
Page 4 of 8
the clinical data for that drug has long been under scrutiny, and its approval was controversial.
FDA approval of Sarepta's eteplirsen left investors in a frenzy chasing me-too stories, and
AveXis became a beneficiary.
Despite Sarepta's stock price being cut in half from its post-approval highs, Citron notes the
key differences between the two companies:
There was no alternative therapy even suggested for treating DMD. For
SMA, Nusinersen has already filed for multiple approval indications.
Sarepta actually monitors Dystrophin as a biomarker to directly measure
efficacy. AveXis has shown no chemical marker of its treatment's method
of action, relying only upon a clinician's subjective observations of
patients at a single center.
Sarepta had very clear inclusion/exclusion criteria to insure a
homogenous patient group. AveXis's study has serious disclosure
deficiencies in its tiny patient cohort that could be skewing its results.
Lastly and most important, the patient advocacy groups for SMA babies are actively trying to
advocate for fast approval of Nusinersen, but NOT AveXis-101.
http://thefastmovement.org/wp-content/uploads/Nusinersen-The-Case-for-FDA-Approval-Now1.pdf
What looks like Clinical Medicine and what looks like a Stock Promotion:
To illustrate how one-sided this argument really is just go to Google News and search the word
Nusinersen. The following 4 articles are from the past week alone on Nusinersen:
SMA Today: http://smanewstoday.com/2016/12/08/nusinersen-safely-treats-infants-with-type-1-sma-study-reports
Stanford Medical Center: http://med.stanford.edu/news/all-news/2016/12/stanford-patient-is-first-infant-to-receive-lifesavingdrug.html
Science Magazine:
http://www.sciencemag.org/news/2016/12/novel-drug-rescues-babies-fatal-neurodegenerative-disease
YETwhen you Google "AveXis" or "AVXS-101", all you can find is a series of articles about the
stock...
https://www.google.com/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-8#tbm=nws&q=AveXis
Page 5 of 8
https://www.google.com/search?hl=en&gl=us&tbm=nws&authuser=0&q=AVXS-101&oq=AVXS-101&gs_l=newscc.3..43j0j43i53.1510.4916.0.5589.10.4.1.5.5.0.79.255.4.4.0...0.0...1ac.1.PnIBT8YWXsI
The science behind AveXis's stock has captured the hope of only the
investment bankers ... and the hospital who has a vested interest in
AveXis's share price...
Conclusion
Given the extremely shady backgrounds of AveXis management and the dubious track records
of the lead investigators at the single clinical site at which its drug is trialed, investors need to
apply professional skepticism to the much-touted "two babies sitting up" claim in AveXis's trial
findings, absent any proof that these babies in fact were symptomatic for SMA Type 1 disease.
Bear in mind that this finding is dependent upon only subjective CHOP-INTEND behavioral
scoring. There is no biochemical analysis of the subjects' condition in this clinical evaluation.
Meanwhile, the anticipated Spring 2017 approval of Biogen/Ionis's competitor drug with
overwhelming safety and efficacy data looms over this company.
With only 240 cases of SMA Type 1 in the USA per year, there is not room for another
competing drug that does not show SUPERIORTITY over Nusinersen. Synergy is not sufficient,
because there is no ethical rationale for a blinded study.
The open label biased testing of AveXis will soon be exposed to the stock market as obviously as
it has already been exposed to the scientific community.
Page 6 of 8
Appendix: AVXS-101
For the science types who want to forego logic, and still want to the believe AveXis investment
thesis, it is time to demand the company reveals some real science and not just observational
CHOP-INTEND scores.
Here is a good start -- and Yes, Citron assembled this with a team of science consultants:
Specific genotypes (genetic testing results) for each child. This should include
information about so called helper genes which the literature has
suggested result in milder cases. (more detail can be found in the
Mako report). Their protocol speaks to a very specific genotype (one of
many genotypes that are all considered SMA) that became an
exclusion criteria once they had treated 10 kids due to the predicted
mild phenotype (aka severity) associated with that genotype. So the
company cant claim it doesnt have all this information. Nor can it
claim that it isnt aware that specific genotypes matter as far as disease
severity. Nor can they claim HIPAA since they put the pictures of the
kids in every presentation they can.
Biological proof that the drug is doing what is claimed. Nusinersen shows that
treated kids have 2x to 5X increase in mRNA (mRNA leads to protein
synthesis) compared with kids that dont. Not only does AVXS not have
any of this data, they have no means of collecting it. That would
require them to get CSF (cerebrospinal fluid) obtained by a lumbar
puncture which their protocol makes no mention of. So they arent
even checking to see if the drug got to its intended target location or if
it worked. They just want us to rely on the CHIP-INTEND scores and
developmental observations. As Citron mentioned previously, even
SRPT had a whiff of dystrophin when they biopsied the muscles. Doing
a protocol revision to get some CSF would not be a big deal at all.
The actual complete FDA minutes from their recent meeting. Again, since
they are expecting us to believe that they can get approved on a 15
patient study, every tiny bit of data matters. Let us judge for ourselves
what the FDA thinks about their trial design. Letting a company move
Citron Dissects AveXis
Page 7 of 8
forward on a trial design does not mean the FDA agrees with it and
there might be some telling language in there. But they wont let the
public see it, so who knows!?!?
The physicians clinical report for the two walkers at baseline. The protocol
requires the kids to have copies of SMN2 and show clinical signs of the
disease. The issue with this is that babies known to have two copies of
the gene are naturally going to be scrutinized with expectation of
seeing any sign of disease whether it exists or not. What appears to be
the case is that the two walkers were not showing ANY real signs of the
disease (their CHOP-INTEND scores were well in the normal range for
children their age again, the Mako report has the details).
The net result of this is the looming risk of study bias by cherry-picked
patients. It is quite clear in the literature that not all kids with two
copies develop the severe form of SMA. Its only without the benefit of
hindsight, and without the support of approved high-efficacy drugs,
that anyone can get away with assuming that two-copies patients will
always progress to severe disease. So if they want us to believe these
two kids were unalterably headed toward a bad prognosis, they
certainly havent done a good job of documenting it.
Page 8 of 8